Natural products as leads for anticancer drug discovery: discovery of new chemotypes of microtubule stabilizers through reengineering of the epothilone scaffold

Epothilones are bacterial macrolides with potent microtubule-stabilizing and antiproliferative activity, which have served as successful lead structures for the discovery of several clinical candidates for cancer treatment. Overall, seven epothilone-type agents have been advanced to clinical evaluation in humans so far and one of these has been approved by the FDA in 2007 for clinical use in breast cancer patients. Notwithstanding these impressive numbers, however, the structural diversity represented by the collection of epothilone analogs that have been (or still are) investigated clinically is rather limited and their individual structures show little divergence from the original natural product leads. In contrast, we have elaborated a series of epothilone-derived macro-lactones, whose overall structural features significantly deviate from those of the natural epothilone scaffold and thus define new structural families of microtubule-stabilizing agents. Key elements of our hypermodification strategy are the change of the natural epoxide geometry from cis to trans, the incorporation of conformationally constrained side chains, the removal of the C(3)-hydroxyl group, and the replacement of C(12) with nitrogen. The latter modification leads to aza-macrolides that may be described as 'non-natural natural products'.

Workshop on FAMIX and Moose in Software Reengineering (FAMOOSr 2008)

The increasing amount of data available about software systems poses new challenges for re- and reverse engineering research, as the proposed approaches need to scale. In this context, concerns about meta-modeling and analysis techniques need to be augmented by technical concerns about how to reuse and how to build upon the efforts of previous research. Moose is an extensive infrastructure for reverse engineering evolved for over 10 years that promotes the reuse of engineering efforts in research. Moose accommodates various types of data modeled in the FAMIX family of meta-models. The goal of this half-day workshop is to strengthen the community of researchers and practitioners who are working in re- and reverse engineering, by providing a forum for building future research starting from Moose and FAMIX as shared infrastructure.

Workshop on FAMIX and Moose in Software Reengineering (FAMOOSr 2009)

The increasing amount of data available about software systems poses new challenges for re- and reverse engineering research, as the proposed approaches need to scale. In this context, concerns about meta-modeling and analysis techniques need to be augmented by technical concerns about how to reuse and how to build upon the efforts of previous research. MOOSE is an extensive infrastructure for reverse engineering evolved for over 10 years that promotes the reuse of engineering efforts in research. MOOSE accommodates various types of data modeled in the FAMIX family of meta-models. The goal of this half-day workshop is to strengthen the community of researchers and practitioners who are working in re- and reverse engineering, by providing a forum for building future research starting from MOOSE and FAMIX as shared infrastructure.

Object-Oriented Reengineering Patterns

The rapid growth of object-oriented development over the past twenty years has given rise to many object-oriented systems that are large, complex and hard to maintain. Object-Oriented Reengineering Patterns addresses the problem of understanding and reengineering such object-oriented legacy systems. This book collects and distills successful techniques in planning a reengineering project, reverse-engineering, problem detection, migration strategies and software redesign. The material in this book is presented as a set of "reengineering patterns" --- recurring solutions that experts apply while reengineering and maintaining object-oriented systems. The principles and techniques described in this book have been observed and validated in a number of industrial projects, and reflect best practice in object-oriented reengineering.

Ranking Software Artifacts

Reengineering and integrated development plat- forms typically do not list search results in a particularly useful order. PageRank is the algorithm prominently used by the Google internet search engine to rank the relative importance of elements in a set of hyperlinked documents. To determine the relevance of objects, classes, attributes, and methods we propose to apply PageRank to software artifacts and their relationship (reference, inheritance, access, and invocation). This paper presents various experiments that demonstrate the usefulness of the ranking algorithm in software (re)engineering.

Evaluating Code Duplication to Identify Rich Business Objects from Data Transfer Objects

Java Enterprise Applications (JEAs) are complex software systems written using multiple technologies. Moreover they are usually distributed systems and use a database to deal with persistence. A particular problem that appears in the design of these systems is the lack of a rich business model. In this paper we propose a technique to support the recovery of such rich business objects starting from anemic Data Transfer Objects (DTOs). Exposing the code duplications in the application's elements using the DTOs we suggest which business logic can be moved into the DTOs from the other classes.

Object-Oriented Legacy System Trace-based Logic Testing

When reengineering legacy systems, it is crucial to assess if the legacy behavior has been preserved or how it changed due to the reengineering effort. Ideally if a legacy system is covered by tests, running the tests on the new version can identify potential differences or discrepancies. However, writing tests for an unknown and large system is difficult due to the lack of internal knowledge. It is especially difficult to bring the system to an appropriate state. Our solution is based on the acknowledgment that one of the few trustable piece of information available when approaching a legacy system is the running system itself. Our approach reifies the execution traces and uses logic programming to express tests on them. Thereby it eliminates the need to programatically bring the system in a particular state, and handles the test-writer a high-level abstraction mechanism to query the trace. The resulting system, called TESTLOG, was used on several real-world case studies to validate our claims.

Using Smalltalk as a Reflective Executable Meta-Language

Object-oriented meta-languages such as MOF or EMOF are often used to specify domain specific languages. However, these meta-languages lack the ability to describe behavior or operational semantics. Several approaches used a subset of Java mixed with OCL as executable meta-languages. In this paper, we report our experience of using Smalltalk as an executable and integrated meta-language. We validated this approach in incrementally building over the last decade, Moose, a meta-described reengineering environment. The reflective capabilities of Smalltalk support a uniform way of letting the base developer focus on his tasks while at the same time allowing him to meta-describe his domain model. The advantage of our this approach is that the developer uses the same tools and environment

Package Patterns for Visual Architecture Recovery

Recovering the architecture is the first step towards reengineering a software system. Many reverse engineering tools use top-down exploration as a way of providing a visual and interactive process for architecture recovery. During the exploration process, the user navigates through various views on the system by choosing from several exploration operations. Although some sequences of these operations lead to views which, from the architectural point of view, are mode relevant than others, current tools do not provide a way of predicting which exploration paths are worth taking and which are not. In this article we propose a set of package patterns which are used for augmenting the exploration process with in formation about the worthiness of the various exploration paths. The patterns are defined based on the internal package structure and on the relationships between the package and the other packages in the system. To validate our approach, we verify the relevance of the proposed patterns for real-world systems by analyzing their frequency of occurrence in six open-source software projects.